My goal is to be an academic vascular surgeon who has an independent research laboratory and teaches vascular surgery in a university setting. My long-term research interest, including my Ph.D. studies, has been inhibition of vascular smooth muscle Cell proliferation by nitric oxide, a process clinically relevant to vascular surgery. Proliferation of smooth muscle cells is critical to the development of both atherosclerosis and post- surgical disorders such as restenosis and vein graft failure. In this proposal l will use a variety of molecular approaches, including dominant negative mutants and anti sense constructs, as well as analysis of kinase and cyclin activity, to define the intracellular mechanisms involved in the antiproliferative effect of nitric oxide. The Specific Aims are: 1) To examine the role of cyclic necleotides and cyclic necleotide-dependent kinases in mediating the anti-proliferative effects of nitric oxide, 2) To determine the effect of nitric oxide on expression of the cell cycle- dependent proto-oncogenes (e.g. fos, myc, myb) and the potential role of inhibition of proto-oncogene expression in growth inhibition by nitric oxide, 3) To determine the mechanism of induction of the cyclin- dependent kinase inhibitor p21 by nitric oxide and the importance of p21 in mediating growth arrest by nitric oxide. The effects of modulation of these intracellular pathways will be evaluated in cultured smooth muscle cells treated with exogenous nitric oxide. These investigations under the guidance of my sponsors, coupled with the courses, seminars and collaborations in this Research Career Award, will substantially broaden my scientific experience and allow me to approach future problems in vascular biology with a wide array of fundamental experimental techniques. Definition of these mechanisms is important to understanding both the physiologic inhibition of pathologic smooth muscle cell proliferation by endothelium and potential new therapeutic strategies for proliferative vascular disorders.